This invention relates to certain benzenesulfonamides and their use as PDE7 inhibitors.
Cyclic nucleotide phosphodiesterases (PDEs) represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) and guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) to their corresponding inactive 5xe2x80x2-monophosphate metabolites. At least 14 distinct classes of PDE isozymes are believed to exist, each possessing unique physical and kinetic characteristics and each representing a product of a different gene family. These are distinguished using Arabic numerals 1-14. And within each distinct class; there may be two or more distinct sub-types. See reviews by Crocker, I et al, Drugs Today, 35(7), 519-535 (1999), Fawcett, L. et al, PNAS, 97(7), 3702-3703 (2000) and Yuasa, K et al, J Biol Chem., 275(40), 31496-31479 (2000).
The present invention relates to the PDE isozyme which is currently identified as PDE7 or HCP1-PDE. This type 7 isozyme is found in various tissues and in particularly high concentrations in skeletal muscle. Two sub-types have been identified, PDE7A Michaeli, T, et al, J Biol Chem., 268 (17) 12925-12932 (1993); Han, P et al, J Biol Chem. 272(26), 16152-16157 (1997) and PDE7B; U.S. Pat. No. 6,146,876; Gardner, C. et al, Biochem Biophys Res. Commun. 272 (1) 186-192 (2000); and Saski, T. et al, Biochem Biophys Res Commun. 271 (3), 575-583 (2000). Herein these will be referred to collectively as PDE7 unless otherwise stated.
PDE7 inactivates secondary messenger cAMP by hydrolysis and inhibition of PDE7 results in increased levels of cAMP. Inhibition of PDE7 may be useful in the treatment of asthma, rheumatoid arthritis, psoriasis, atopic dermatitis and chronic bronchitis. While assessment of PDE7 message expression indicates a broad cellular distribution, PDE7 protein expression and activity is localized mostly to T-lymphocytes and lymphoid tissue. Consequently, PDE7 inhibitors may be useful in the treatment of T-cell-mediated disorders. Morerover, selective PDE7 inhibitors may have reduced adverse events sometimes encountered with other PDE inhibitors, events such as CNS, GI and cardiovascular side effects.
This invention relates to compounds of Formula 1 for use in the mediation or inhibition of the enzymatic activity (or catalytic activity) of PDE7 in mammals, including humans, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula 1: 
wherein,
R1 is NRaRb where Ra and Rb are independently H or C1-6 alkyl, or xe2x80x94NRaRb represents a 5 to 7 member ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S;
R2 is H, C1-8 alkyl, C1-3 alkyl-Ar, C1-3 alkyl-C3-6 cycloalkyl, C2-8 alkenyl, C2-4 alkenyl-Ar, or C2-4 alkenyl-C3-6 cycloalkyl;
Ar is substituted or unsubstituted phenyl;
R3 is NO2, halo, CN, C(O)OR7, COR1, or NRaRb where Ra and Rb are independently H or C1-6 alkyl;
R4 is H, xe2x80x94OC1-6 alkyl, halo, C(O)NRaRb, C(O)OR7, C1-8 alkyl, xe2x80x94OCHF2, xe2x80x94CH2 OR8, xe2x80x94OC1-3 alkylAr, or CH2NHC(O)CH3;
R5 is H, halo, or alkyl;
R6 is C1-8 alkyl, OC1-4 alkyl or halo;
R7 is hydrogen or an ester or amide-forming group;
R8 is hydrogen or C1-6 alkyl;
or a pharmaceutically acceptable salt or solvate thereof.
Included in this invention are the novel compounds of Formula 1 and pharmaceutically acceptable formulations thereof.
These PDE7 inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases including: asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, and chronic glomerulonephritis.
As regards preferred embodiments of the compounds disclosed herein, the following groups are preferred:
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo. The preferred halo groups are chloro and bromo.
xe2x80x9cAlkenylxe2x80x9d refers to an unsaturated straight or branched hydrocarbon chain, which has 1 or more double bonds. Preferred groups are substituted ethenyl.
In R1, Ra or Rb is preferably hydrogen or lower alkyl, or NRaRb is a 5-or 6-membered ring with or without a heteroatom. When Ra or Rb is an alkyl group it is preferred that it be methyl or ethyl. Where R1 is NRaRb is a ring, the ring may be, for example: 1-imidazolyl, 2-R(7)-1-imidazolyl, 1-pyrazolyl, 3-(R7)-pyrazolyl, 1-triazolyl, 2-triazolyl, 5-(R7)-1-triazolyl, 5-(R7)-2-triazolyl, 5-(R7)-1-tetrazolyl, 5-(R7)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4-(R7)-1-piperazinyl, pyrrolidinyl or pyrrolyl where R7 is hydrogen or C1-4 alkyl. The most preferred rings are morpholinyl and pyrrolidinyl.
Preferred R2 groups are hydrogen, C1-8 alkyl or C1-3 alkyl-Ar where Ar is phenyl unsubstituted or substituted by C(O)OR7.
Preferred R3 groups are NO2, Cl, Br, or NRaRb where Ra and Rb are independently H or C1-6 alkyl.
R4 is preferably hydrogen, xe2x80x94OC1-6 alkyl, Cl, C(O)NRaRb, C1-4 alkyl, xe2x80x94OCHF2, xe2x80x94CH2OR8, or xe2x80x94OC1-3 alkylAr where Ar is phenyl, unsubstituted or substituted by C(O)OR7.
R5 is preferably hydrogen.
R6 is preferably Cl, Br or methyl.
Compounds disclosed herein include the following:
2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-methyl-5-nitropyrrolidinylbenzenesulfonamide;
2-methyl-5-nitromorpholinobenzenesulfonamide;
2,4-dimethyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-ethyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-methoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-(3-carboxybenzyloxy)-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-difluoromethoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-bromo-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-amido-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
4-methyleneoxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide;
2-methyl-4-(methyl)methyleneoxy-5-nitro(N,N-dimethyl)benzenesulfonamide;
5-chloro-2-methyl(N,N-dimethyl)benzenesulfonamide;
2,5-dichloro-4-methyl(morpholino)benzenesulfonamide;
4,5-dichloro-2-methyl(N,N-dimethyl)benzenesulfonamide;
2,4,5-trichloro(N,N-dimethyl) benzenesulfonamide;
2,5-dichloro-4-methoxy(N, N-dimethyl)benzenesulfonamide;
2,5-dichloro-4-difluoromethoxy(N,N-dimethyl)benzenesulfonamide;
5-bromo-2-methyl(N,N-dimethyl) benzenesulfonamide;
2-bromo-5-cyano(N,N-dimethyl)benzenesulfonamide;
3-N,N-dimethylamino-2-methyl(N,N-dimethyl)benzenesulfonamide;
methyl 2,5-dichloro-4-(N-morpholino)sulfonyl benzoate;
2,5-dichloro-4-methyleneoxy(morpholino)benzenesulfonamide;
2,5-dichloro-4-(methyl) methyleneoxy(morpholino)benzenesulfonamide;
3,6-dichloro-2-methyl-4-methyleneoxy(morpholino)benzenesulfonamide;
3,6-dichloro-2-(3-methoxy)phenethyl-4-methyleneoxy(morpholino)benzenesulfonamide; or
N-(2,5-dichloro-4-morpholinosulfonyl)benzyl acetamide.
The present compounds and pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, dermally, transdermally, rectally, via inhalation or via buccal administration. A controlled-release preparation can also be utilized. An orally administered preparation is preferred.
The present compounds and pharmaceutically acceptable salts, which are active when given orally, can be formulated as syrups, tablets, capsules, controlled release preparation, or lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, and peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
A typical suppository formulation comprises the present compound or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
Each dosage unit for oral administration contains suitably from 0.3 mg to 60 mg/Kg, and preferably from 1 mg to 30 mg/Kg of a compound or a pharmaceutically acceptable salt thereof. Preferred doses include 10 mg and 15 mg/Kg. Each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg/Kg, of the compound or a pharmaceutically acceptable salt thereof. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 5.0% of a present compound.
The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredient is administered about once or twice a day, more preferably once a day.
Compounds of the Formula 1 wherein R1 is exemplified by N(CH3)2 is H, R3 is NO2, R4 is OH, OCH3, OCF2H; R5 is H, and R6 is CH3 may be prepared by methods analogous to those described in Scheme 1. 
Arylsulfonyl chlorides, such as 2-Scheme-1, may be prepared from 5-methyl-2nitrophenol (available from Aldrich Chemical Co.) by conventional means such as treatment with chlorosulfonic acid. 2-Scheme-1 can be aminated by treatment with an excess of amine (such as dimethylamine) in a solvent such as methanol. Aryl ethers such as 4-Scheme-1 can be prepared by heating the phenol 3-Scheme-1 with a base such as cesium carbonate and the desired alkylating agent (such as dimethylsulfate) in an aprotic solvent such as DMF. The difluoromethyl ether 5-Scheme-1 can be prepared by refluxing phenol 3-Scheme-1 with sodium hydroxide and chlorodifluoroacetic acid in dimethylformamide.
Compounds of the formula 1 wherein R1 is NRaRb (where RaRb is H or alkyl), or xe2x80x94NRaRb together with the nitrogen form a 5 to 7 member ring comprised of carbon or carbon and one or more additional heteroatoms selected from O, N, or S; R2 is H; R3 is NO2, Cl, Br, CN, COOH; R4 is H, OH, halo, C1-8 alkyl; R5 is H, halo, or alkyl; R6 is C1-8 alkyl, an ether, or halo are prepared in an analogous manner to 3-Scheme-1, except substituting the appropriate aryl starting material. 
Conversion of the phenol into a carbon-based functionality can be accomplished by treating phenol 1-Scheme-2 with trifluoromethanesulfonic anhydride and triethylamine in dry methylene chloride. The resulting triflate can then be treated with tetrabutylammonium bromide in refluxing toluene to provide the halo-sulfonamide 2-Scheme-2. Formation of the amido-sulfonamide 4-Scheme-2 is accomplished by heating the halo sulfonamide 2-Scheme-2 with CuCN under argon in dry dimethylformamide, followed by hydrolysis of the resulting nitrile compound with a basic aqueous hydrogen peroxide solution. Preparation of the benzyl alcohol 6-Scheme-2 results from hydrolysis of the amido-sulfonamide to the carboxylate, followed by standard BH3 in THF reduction conditions. The methyl ether 7-Scheme-2 is obtained by treatment of alcohol 6-Scheme-2 with dimethyl sulfate in methylene Chloride and 1 N NaOH under phase-transfer conditions using benzyltriethylammonium chloride as the phase transfer agent. 
Compounds of the formula I wherein R1 is morpholino, R2 is H, R3 and R6 are Cl, R4 is an alcohol or ether; and R5 is H are prepared by a procedure analogous to Scheme 3. Alcohol 3-Scheme-3 is prepared by oxidation of dichloro-methyl compound 1-Scheme-3 with an oxidzing agent such as KMnO4 in basic aqueous solution, followed by ester formation with catalytic acid in methanol, followed by ester reduction with a suitable reducing agent such as Dibal to provide the alcohol. Formation of methyl ether 4-Scheme-3 is performed in a manner analogous to 7-Scheme-2. 
Formation of methyl compound 4-Scheme-4 is accomplished by protecting alcohol 1-Scheme-4 (3-Scheme-3) with the likes of a silyl protecting group (such as tert-butyldimethylsilyl) using standard procedures well known in the art. Deprotonation of the ortho-position to the sulfonamide with a strong base such as n-butyllithium in an aprotic solvent under anhydrous conditions, followed by addition of methyl iodide provides the protected methyl-compound 3-Scheme-4. Removal of the silyl group by treatment with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) provides the alcohol 4-Scheme-4. Likewise, formation of the phenethyl compound 6-Scheme-4 can be accomplished in a similar manner by deprotonation of the methyl group of protected sulfonamide 3-Scheme-4 with a strong base under anhydrous conditions, followed by addition of 3-methoxybenzyl chloride. Deprotection of the alcohol with TBAF in THF provides the phenethyl-substituted benzenesulfonamide 6-Scheme-4.
Compounds of the Formula 1 wherein R4 is exemplified by CH2 NHC(O)CH3 are prepared by methods analogous to those described in Scheme 5. 
Bromination of sulfonyl chloride 1-Scheme-5 with n-bromosuccinamide (NBS), followed by treatment with morpholine provides benzyl bromide, 2-Scheme-5. Reaction of this bromide with ammonium hydroxide results in amine 3-Scheme-5. Amides such as 4-Scheme-5 may be prepared by conventional procedures for amide formation, such as treatment with an acid chloride (such as acetyl chloride) or using standard coupling procedures with a carboxylic acid (such as EDC and acetic acid).
The following examples are given to illustrate, but not limit, the invention described and claimed herein.
No deleterious or untoward effects are expected to occur when this invention is used in accordance with the teachings set forth herein.